Bisarenes such as biaryls and styrenes are common components of many high value molecules such as pharmaceuticals, asymmetric conducting polymers, ligands and dyes for organic light emitting diodes as shown in FIG. 1. Two of the methods of choice, both in industry and academia, for the synthesis of these compounds are the Suzuki and Heck reactions, respectively. These reactions often work well; however, the overall process required to form an aryl-aryl or aryl-olefin bond is inherently inefficient, and it is far from ideal. Common coupling reactions, such as the Suzuki reaction, require that each of the substrates be pre-functionalized with groups such as boronic acids and bromides before the coupling reaction can occur. This adds extra steps to the overall synthesis of target molecules like those shown in FIG. 1. The current practice of installing these functional groups and then discarding them after the coupling reaction is inefficient and results in the production of large amounts of chemical waste. The generation and disposal of this waste has large economic and environmental impacts.
Carbon-hydrogen (C—H) bonds are ubiquitous in organic molecules, and, as a general rule, these C—H bonds are unreactive. That is why the Suzuki reaction requires the presence of boronic acids and bromides. However, for the reasons previously stated, the ideal synthetic process would not use these functional groups, it would simply couple the carbons of two C—H bonds to form a new C—C bond. Oxidative couplings of this type are rare and, as such, represent an underdeveloped, but potentially valuable, area of organic chemistry (Scheme 1).

The oxidative couplings that have been previously reported can be divided into four categories based on their mechanisms: ionic, radical, organometallic deprotonation, and C—H activation. In each case, a stoichiometric oxidant is required for catalyst turnover. Examples of common oxidants are peroxides, olefins, and molecular oxygen (O2).
Recently, numerous oxidative couplings (often called cross-dehydrogenative couplings) have been performed via the in situ formation of iminium ions. These intermediates are often formed via oxidation of the weak sp3-hybridized C—H bonds of N,N-disubstituted benzylamines, such as N-phenyl tetrahydroisoquinolin, followed by the attack of a nucleophile. Notable recent work in this field has been performed by Li using nucleophiles such as indole, malononitrile, and nitromethane. Additionally, Li has recently described a method for oxidatively coupling allylic C—H bonds with malonate nucleophiles using a combination of cobalt and copper catalysts. In each of these examples, the terminal oxidant is tert-butyl hydroperoxide.
Radical mechanisms have also been employed in the oxidative formation of C—C biaryl bonds. Often these processes use stoichiometric amounts of radical initiators such as FeCl3, and are used to synthesize polymers such as polythiophenes. This work has even been adapted to form chiral binapthalenes using asymmetric vanadium or copper catalysts and aerobic conditions. Recently, Yu has described a copper catalyzed reaction that oxidatively forms C—C, C—N, C—O, C—S, C—Cl, and C—Br bonds. Though extensive mechanistic studies of this process have not been performed, a radical pathway has been proposed.
Early work in the field of oxidative coupling used stoichiometric amounts of Pd(II) salts. These palladium complexes oxidatively couple by effectively deprotonating two aryl C—H moieties to form [Ar—Pd—Al] intermediates. Subsequently, the C—C bond is formed by reductive elimination. Alternatively, a Heck-type mechanism can be followed after one C—H deprotonation to form a styrene-type bond. Fujiwara performed noteworthy examples of this for the formation of styrenes. Additionally, Itahara used stoichiometric Pd(II) salts to couple electron-rich heteroarenes like furan with benzene, albeit in poor yields. Recently, Stolz used a stoichiometric amount of Pd(II) to perform the key oxidative coupling in his synthesis of dragmacidin. As with the Wacker oxidation, it was soon discovered that molecular oxygen could be used as the terminal oxidant when copper or silver cocatalysts were added: A notable example of this is the work of Gaunt, which demonstrated a Pd(II)—Cu(II)—O2 method for regioselectively alkenylating either the 2- or 3-position of indole. Recently, Ishii has discovered that phosphomolybdovanadic acids (HPMVs) are effective co-catalysts allowing for hundreds of catalytic turnovers. However, this HPMV-Pd(II) system has only been applied to the synthesis of biphenyl and cinnamates.
Arene-arene coupling using aerobic conditions is also a known process. However, it has only been used to synthesize dimeric products like biphenyl. Ishii has also used this system to couple olefins to each other. Interestingly, when equal amounts of electron-poor and electron-rich olefins were subjected to the oxidative conditions, very little dimerization was observed. Rather, the cross-products were favored. While Ishii does not explain this unique observation, it corroborates the interesting preliminary results that have been observed in our laboratory.
In addition to the palladium-catalyzed oxidative couplings that have been described herein, it should be noted that several research groups are currently pursuing the formation of C—C bonds via palladium catalyzed C—H/C-halogen couplings. While these processes are not formally oxidative, they provide insights into the mechanism of oxidative coupling. The majority of work in this field has utilized electron-rich arenes, as they are readily metallated by electrophilic Pd(II) catalysts. However, Maseras and Echavarren have used an intramolecular competition experiment to show that an electron-poor pyridine ring was selectively palladated in the presence of a phenyl ring (selectivity=2.1:1). Larock, Echavarren, and Gallagher have observed selectivity for the substitution of electron-poor arenes in Pd-migrations and couplings within biaryl moieties. Fagnou has exploited this phenomenon by developing a coupling reaction between pentafluorobenzene and bromobenzene. Maseras and Echavarren as well as Fagnou used computational modeling to provide insight into their observations. In both cases, it was concluded that the key C—H functionalization step did not proceed via palladium-mediated electrophilic aromatic substitution. Rather it involved the direct deprotonation of the arene's C—H bond following coordination of the arene to an electrophilic palladium intermediate. These experiments have produced a new paradigm through which aromatic palladations may be viewed.
In addition to the palladium-catalyzed oxidative couplings that form C—C bonds, aerobic oxidative coupling reactions have been developed to form C—N and C—O bonds. Most of these reactions involve the nucleophilic attack of an amide or alcohol nucleophile on an olefin that has been activated by coordination to a Pd(II) catalyst. While this mechanism is significantly different from those of the oxidative couplings proposed herein, these reactions involve the aerobic regeneration of catalytic Pd(II) species from Pd(O) intermediates. Work in this field has demonstrated that this oxidation process is significantly enhanced by the presence of carboxylic acids and/or coordinating solvents such as pyridine or DMSO.
A few examples of C—N and C—O formation do not involve electrophilic olefin-Pd(II) complexes. Notably, Sanford has shown that arenes and even alkanes can be oxidized to C—O, C—Cl, C—Br, and even C—C species using strong oxidants such as PhI(OAc)2. She has rigorously shown that these reactions proceed though Pd(II)/Pd(IV) mechanisms. Recently, Buchwald showed that Pd(OAc)2/Cu(OAc)2 catalyzed the aerobic formation of carbazoles from 2-amino biphenyls. This reaction presumably proceeds via a mechanism that is similar to our preliminary results.
While significant advances in the field of oxidative coupling have been observed, the method as a whole is still rarely used for organic synthesis. A survey of the current chemical literature quickly reveals that the method of choice for the synthesis of bis-arenes and styrenes is still the Suzuki reaction—although C—H/C-halide coupling reactions are becoming increasingly important. The reasons for the lack of oxidative couplings are likely their limited substrate scope and their relatively high catalyst loadings